GRanulocyte Augmented Cord Blood Transplantation for Poor Risk leukaEmia

NCT07372885 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 357519
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief Summary

Allogeneic stem cell transplantation is the only potentially curative therapy for patients with high-risk Acute Myeloid Leukaemia, but relapse is common and remains the leading cause of death. Patients with certain mutations and those transplanted without first clearing their disease have very poor outcomes with most relapsing soon after transplant, and then surviving only a few months. A recent trial at the Royal Manchester Children's Hospital used cord blood stem cells alongside a type of white blood cell called 'granulocytes' and produced surprisingly good outcomes for children with very resistant leukaemia. GRACE is a clinical trial for adults (\<55 years) with Acute Myeloid Leukaemia that has not responded to chemotherapy or harbours mutations that predict a very poor response to conventional transplant. Participants will receive a transplant using umbilical cord blood and be given additional infusions of white blood cells, called granulocytes. The trial will be split into two parts:-The first will study the safety of this new approach. The experience of the investigators in children is that granulocyte infusions cause a fever, rash and expansion of another type of white blood cell called lymphocytes. Children that did not have this reaction did not respond to treatment. The investigators therefore believe that the reaction is necessary for the treatment to work, but the investigators must ensure that it is safe in adult patients. The trial design allows the investigators to determine the dose of granulocytes that is best tolerated and most likely to be effective. The aim of the second part is to demonstrate that the new treatment is more effective than conventional transplantation. The study will be conducted in three NHS transplant centres. Patients will be recruited over 36 months and followed up for a minimum of 1 year. The study is funded by Blood Cancer UK.

Conditions

Acute Myeloid Leukemia; Stem Cell Transplantation; Stem Cell Transplantation, Hematopoietic; Cord Blood Stem Cell Transplantation; Cellular Therapy

Keywords

Grace; granulocyte-augmented cord blood transplantation; poor risk acute myeloid leukaemia; Cord Blood Transplantation; Myelodysplastic Syndrome; TP53; MECOM

Outcome Measures

Primary Outcomes (6)

• Frequency and Severity of Cytokine Release Syndrome (CRS)

  Frequency and Severity of Cytokine Release Syndrome (CRS) assessed via ASTCT Consensus Grading for CRS

  Day 0 (day of allograft) to Day 28 post allograft

• Frequency and Severity of Acute Graft vs Host Disease

  Frequency and Severity of Acute Graft vs Host Disease assessed by modified Glucksberg criteria (revised by MAGIC)

  Day 0 (day of allograft) to Day 100 post allograft

• Frequency and Severity of Chronic Graft vs Host Disease

  Frequency and Severity of Chronic Graft vs Host Disease assessed by NIH criteria

  Day 100 post allograft to Day 360 post allograft

• Frequency of Transplant Related Mortality (TRM)

  Frequency of Transplant Related Mortality (TRM) defined as death due to any transplantation-related cause other than disease relapse

  Day 0 (day of allograft) to Day 100 post allograft

• Frequency of Primary Graft Failure

  Frequency of Primary Graft Failure

  Day 0 (day of allograft) to Day 28 post allograft

• Rate of Relapse-Free Survival (RFS)

  Relapse-free survival (RFS) rate: number of patients who remain relapse-free and alive within 1 year from transplant

  Day 0 (day of allograft) to Day 360 post allograft

Secondary Outcomes (3)

• Frequency of Non-Relapse Mortality (NRM)

  Day 0 (day of allograft) to Day 360 post allograft

• Duration of Overall Survival

  Day 0 (day of allograft) to Day 360 post allograft

• Duration of GvHD Free Relapse Free Survival (GRFS)

  Day 0 (day of allograft) to Day 360 post allograft

Study Arms (5)

Phase I: T replete cord blood transplant + conditioning + 1 day Granulocytes

ACTIVE COMPARATOR

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given to participants for 1 day starting on the day of transplant.

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Phase I: T replete cord blood transplant + conditioning + 3 day Granulocytes

ACTIVE COMPARATOR

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 3 days starting on the day of transplant.

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Active Comparator: Phase I: T replete cord blood transplant + conditioning + 5 day Granulocytes

ACTIVE COMPARATOR

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 5 days starting on the day of transplant.

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Active Comparator: Phase I: T replete cord blood transplant + conditioning + 7 day Granulocytes

ACTIVE COMPARATOR

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to participants for 7 days starting on the day of transplant.

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Phase II: T replete cord blood transplant + conditioning + Granulocytes at Recommended Phase II Dose

EXPERIMENTAL

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to all participants- at the Recommended Phase II Dose (RP2D)

Biological: Cord blood transplantation + conditioning + granulocytes of variable days according to study design

Interventions

Cord blood transplantation + conditioning + granulocytes of variable days according to study design BIOLOGICAL

All participants will receive a T replete cord blood transplant with a standardised conditioning regimen involving Fludarabine, Cyclophosphamide, Thiotepa, and TBI. A single pool of irradiated granulocytes will be given daily to all participants- but for a variable number of days starting on the day of transplant according to study design (1,3,5 or 7 days). The study consists of two phases- Phase 1 has two components (dose escalation and dose optimisation) to identify the Recommended Phase II Dose (RP2D) of granulocytes. Phase 2 will assess preliminary efficacy based Relapse Free Survival at 1 year.

Active Comparator: Phase I: T replete cord blood transplant + conditioning + 5 day Granulocytes; Active Comparator: Phase I: T replete cord blood transplant + conditioning + 7 day Granulocytes; Phase I: T replete cord blood transplant + conditioning + 1 day Granulocytes; Phase I: T replete cord blood transplant + conditioning + 3 day Granulocytes; Phase II: T replete cord blood transplant + conditioning + Granulocytes at Recommended Phase II Dose

Eligibility Criteria

• Age: 16 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Availability of a suitable cord blood unit
• Age between 16 and 55 years
• Primary diagnosis of Acute Myeloid Leukaemia (AML) or MDS/AML (as defined by ICC 2022) fitting one or more of the following criteria:
• TP53 mutation (single- or multi-hit)
• Presence of inv(3) (q21.3q26.2) or t(3;3)(q21.3;q26.2)
• Adverse risk (as per ICC 2022) and \>0.1% MRD by flow cytometry after 2 cycles of induction
• AML (any risk) with partial remission (\<10% blasts) after 2 cycles induction
• Early relapse (\<6 months) after chemotherapy alone (excluding t(16;16), inv(16) or t(8;21))
• Bone marrow performed within 28 days of starting conditioning chemotherapy demonstrates either:
• \<10% blasts
• \>10% blasts with a hypocellular background (must be discussed with the trial team)
• Suitable fitness and organ function as per the following criteria:
• Glomerular filtration rate \>50 mL/min/1.73m2
• Ejection fraction \>50%
• FEV1 \>65% without dyspnoea on mild activity

You may not qualify if:

• AML Secondary to a myeloproliferative neoplasm
• Active CNS disease
• Prior allogeneic stem cell transplant
• Participation in another clinical trial that would alter any aspect of the transplant protocol or that aims to reduce the subsequent risk of relapse (discuss with trial team if unsure)
• History of cardiac arrhythmia
• Ischaemic heart disease, valvular heart disease or congestive cardiac failure
• Transient ischaemic attack or cerebrovascular accident
• Rheumatologic disease (SLE, RA, polymyositis, mixed CTD or polymyalgia rheumatica)
• Ulcerative colitis or Crohn's disease
• Liver cirrhosis
• Presence of an active second malignancy
• Uncontrolled infection, including viral reactivation (CMV, EBV)
• HIV positive
• Hepatitis B/C active infection with measurable viral load (patients with chronic hepatitis B or C infection require clear documentation of absence of cirrhosis by either fibroscan or biopsy, regardless of viral load)
• Pregnancy, breastfeeding, unwilling to use contraception

Sponsors & Collaborators

• University of Manchester: lead
• King's College Hospital NHS Trust: collaborator
• Institute of Cancer Research, United Kingdom: collaborator
• The Christie NHS Foundation Trust: collaborator
• Royal Marsden NHS Foundation Trust: collaborator

Study Sites (3)

Kings College Hospital NHS Trust

London, United Kingdom

Location

The Royal Marsden Hospital NHS Foundation Trust

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Study Officials

• Mark Williams, BA MB BChir PhD MRCP FRCPath

  University of Manchester

  PRINCIPAL INVESTIGATOR

• Mili N Shah, BSc MBBS MRCP FRCPath

  Kings College Hospital NHS Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Johnna Ward GRACE Trial Manager

CONTACT

02032999000; kch-tr.gracestudy@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Investigator

Model Details: This trial utilises an innovative early phase seamless design, integrating dose-escalation and randomised dose-optimisation which is built on latest FDA and MDICT guidance. Phase I (up to 30 patients) will include two components: dose-escalation and dose-optimisation to identify the Recommended Phase II Dose (RP2D). In the dose-escalation component, a modified 2-stage Bayesian Time-to-event Continual Reassessment Method (TITE-CRM) will be used to determine the maximum tolerated dose and tolerable doses among 4 dose schedules. In the dose optimisation, subsequent patients will be randomised to selected tolerable doses to determine final RP2D based on tolerability, activity and other key secondary endpoints in consultation with the integrated TSC/DMC. Phase II will assess preliminary efficacy at the RP2D, based on relapse free survival at 1 year using a single-stage Bayesian design.

Study Record Dates

• First Submitted: November 20, 2025
• First Posted: January 28, 2026
• Study Start: February 9, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: March 11, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)